1. Field of the Invention
This invention relates generally to anti-human VEGF antibodies with unusually high binding affinity for human VEGF-A and which also cross react with human VEGF-B and particularly to chimeric and humanized versions these antibodies.
2. Description of Related Art
Angiogenesis is a physiological process that involves the growth of new blood vessels from pre-existing ones. This process is vital for growth and development as well as for wound healing. However, it is also fundamental for malignant tumor development and for other non-tumor associated pathologies such as proliferative retinopathies, rheumatoid arthritis and psoriasis (Folkman J. 1971; Praidou A et al. 2010; Canavese M et al. 2010). Vascular endothelial growth factor (VEGF) is a protein secreted by stromal and tumor cells and in a minor proportion by a variety of other cells that plays a key role in stimulation of Angiogenesis (Ferrara N et al. 2004). Over-expression of VEGF can contribute to angiogenesis related diseases. For example, solid cancers cannot grow beyond a limited size without an adequate blood supply and cancers that express VEGF are more capable of growing and metastasizing (Ferrara N. 2005). Taking into account these considerations, anti-angiogenic therapies were developed using anti-VEGF monoclonal antibodies such as Bevacizumab (AVASTIN™) for cancer treatment (Ferrara N et al. 2005) and Ranibizumab (LUCENTIS™) for retinopathy (Ciulla T A et al. 2009). Therapies based in the use of Bevacizumab and Ranibizumab have been extensively studied and applied during the last few years (Van Meter M E et al. 2010; Ciulla T A et al. 2009). Bevacizumab was approved by the U.S. Food and Drug Administration (FDA) for metastatic renal carcinoma, glioblastoma, metastatic colon cancer and non-small cell lung cancer in combination with standard chemotherapy and for use in metastatic breast cancer. However, in the US, a FDA panel of experts has now said they do not see enough of a benefit from AVASTIN™ in advanced breast cancer to justify its serious risks. Several clinical trials are also currently in progress in non-metastatic breast cancer, renal cell carcinoma, glioblastoma multiforme, ovarian cancer, castrate-resistant prostate cancer, non-metastatic unresectable liver cancer and metastatic or unresectable locally advanced pancreatic cancer. Bevacizumab is also used without FDA approval, but on the basis of clinical studies, for treatment of macular degeneration, an eye disease also characterized by proliferation of blood vessels in the retina. Ranibizumab is a Fab antibody fragment derived from the same murine antibody as Bevacizumab and has been approved by the FDA to treat the wet age-related macular degeneration.
In spite of the benefits resulting of the clinical use of the currently approved anti-VEGF-A antibodies, numerous problems remain to be solved regarding to therapeutic effects, side effects, resistance to treatment and cost of treatments. Therefore, development of new more effective anti-human VEGF antibodies is necessary. We have now developed new anti-human VEGF antibodies witch surprisingly have unusually high binding affinity for the human VEGF-A target and cross-reactivity with human VEGF-B. Even thought VEGF-B is strongly related to VEGF-A according to its amino acid sequence, rather than an angiogenic function has a potent survival/antiapoptotic effect required for blood vessel survival (Li X et al. 2009). Therefore, VEGF-B is very important to maintain integrity of the blood vessels which support tumor growth and interference in its action should contribute to a more complete anti-tumor therapy.